Problem Solving in Diabetes

Problem Solving in

Diabetes LEE KENNEDY James Cook University, Queensland, Australia

ISKANDAR IDRIS Sherwood Forest Hospitals, Sutton-in-Ashfield, UK

A N A S TA S I O S G A Z I S Queen’s Medical Centre University Hospital, Nottingham, UK

CLINICAL PUBLISHING OXFORD

CLINICAL PUBLISHING An imprint of Atlas Medical Publishing Ltd Oxford Centre for Innovation Mill Street, OxfordOX2 0JX, UK T: +44 1865 811116 F: +44 1865 251550 W: www.clinicalpublishing.co.uk Distributed by: Marston Book Services Ltd PO Box 269, Abingdon Oxon OX14 4YN, UK T: +44 1235 465500 F: +44 1235 465555 E: [email protected]

©Atlas Medical Publishing Ltd 2006 First published 2006 All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, without the prior permission in writing of Clinical Publishing or Atlas Medical Publishing Ltd Although every effort has been made to ensure that all owners of copyright material have been acknowledged in this publication, we would be glad to acknowledge in subsequent reprints or editions any omissions brought to our attention A catalogue record for this book is available from the British Library ISBN 1 904392 61 X Electronic ISBN 978 1 84692 565 8 The publisher makes no representation, express or implied, that the dosages in this book are correct. Readers must therefore always check the product information and clinical procedures with the most up-to-date published product information and data sheets provided by the manufacturers and the most recent codes of conduct and safety regulations. The authors and the publisher do not accept any liability for any errors in the text or for the misuse or misapplication of material in this work Project manager: Series design by Pete Russell, Faringdon, Oxon Typeset by Pete Russell, Faringdon, Oxon Printed by TG Hostench S.A., Barcelona

Contents Abbreviations vii S E C T I O N 01 1 2 3 4 5 6

Acute Diabetes

25

Diabetic ketoacidosis 25 Hyperosmolar hyperglycaemic state 30 Recurrent hypoglycaemia 34 Diabetes and acute myocardial infarction 40 Diabetes and acute stroke 43 Diabetes and critical limb ischaemia 47 Perioperative management of diabetes 51 The hot foot 55 SECTION 03

15 16 17 18 19 20 21 22 23

1

Preventing type 1 diabetes 1 Preventing type 2 diabetes 5 Diabetes risk after the menopause 9 Genetic diabetes syndromes (MODY) 13 Screening and impaired glucose tolerance 17 Type A/B diabetes and insulin resistance 21 S E C T I O N 02

7 8 9 10 11 12 13 14

Prevention and Diagnosis

Managing Diabetes

61

Insulin pumps 61 Type 1 diabetes and exercise 65 Adolescent diabetes 69 Low-carbohydrate diets 72 Treatments that stimulate insulin production 77 Treatments that improve insulin resistance 81 Diabetes and enteral feeding 85 Obesity and diabetes 89 Diabetes in the elderly 93 SECTION 04

Reproductive Complications

24 Polycystic ovarian syndrome 99 25 Gestational diabetes 103 26 Type 1 diabetes and pregnancy 107

99

vi

Contents

27 Erectile dysfunction 111 28 Pre-eclampsia 115 SECTION 05 29 30 31 32 33 34 35

149

Macrovascular and Other Complications

187

Angina in patients with type 2 diabetes 187 Advances in management of peripheral arterial disease 191 Renal artery stenosis 195 Foot ulceration 199 Transient ischaemic attack 203 SECTION 08

50 51 52 53

Microvascular Complications

Painful neuropathy 149 Microalbuminuria 154 ACE inhibitor treatment 159 Advancing renal failure 163 Background retinopathy 167 Proliferative and pre-proliferative retinopathy 171 Macular disease 175 Autonomic neuropathy 178 The Charcot foot 182 S E C T I O N 07

45 46 47 48 49

121

Smoking cessation 121 Hypertriglyceridaemia 125 Hyperlipidaemia in type 1 diabetes 129 Hyperlipidaemia in type 2 diabetes 133 Aspirin use in diabetes 137 Hypertension—uncomplicated 140 Hypertension—hard to control 143 SECTION 06

36 37 38 39 40 41 42 43 44

Cardiovascular Risk Factors in Diabetes

Diabetes in Special Groups of Patients

Diabetes and respiratory disease 207 Diabetes and cystic fibrosis 212 Diabetes and dialysis 216 Diabetes and coeliac disease 220

General index 225

207

Abbreviations 4S Scandinavian Simvastatin Survival Study ABCD trial Appropriate Blood Pressure Control in Diabetes Trial ABPI Ankle–brachial pressure index ABPM Ambulatory blood pressure monitoring ACAS Asymptomatic Carotid Atherosclerosis Study ACE Angiotensin-converting enzyme ACR Albumin–creatinine ratio ACHOIS trial Australian Carbohydrate Intolerance Study in Pregnant Women AER Albumin excretion rate AHI Apnoea–Hypopnea Index ALLHAT Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial AMD Age-related macular degeneration ANG-1 and ANG-2 Angiopoetin APT Anti-Platelet Trialists ARB Angiotensin receptor blocker ASTRAL trial Angioplasty and Stent for Renal Artery Lesions trial BARI trial Bypass Angioplasty Revascularization Investigation BMI Body mass index BP Blood pressure CABG Coronary artery bypass grafting CALM study Candesartan And Lisinopril Microalbuminuria study CAPD Continuous ambulatory peritoneal dialysis CAPRIE study Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events study CARDS Collaborative Atorvastatin Diabetes Study CARE study Cholesterol and Recurrent Events study CAS Carotid artery stenosis CETP Cholesteryl ester transfer protein CF Cystic fibrosis CFRD Cystic fibrosis-related diabetes

CHD Coronary heart disease CHHIPS Controlling Hypertension and Hypotension Immediately Post-Stroke trial CI Confidence interval CK Creatine kinase CPAP Continuous positive airway pressure CSII Continuous subcutaneous infusion of insulin CSMO Clinically significant macular oedema CT Computed tomography CWS Cotton-wool spot DAN Diabetic autonomic neuropathy DCCT Diabetes Control and Complications Trial DIGAMI Diabetes and Insulin-Glucose Infusion in Acute Myocardial Infarction study DIRECT DIabetic Retinopathy Candesartan Trial DKA Diabetic ketoacidosis DMa Diabetic maculopathy DME study Diabetic Macular Edema study DPN Distal sensory peripheral neuropathy DPP Diabetes Prevention Program DPP-IV Dipeptidyl peptidase IV DPS Diabetes Prevention Study DRS Diabetic Retinopathy Study ECG Electrocardiogram ECST European Carotid Surgery Trial EDIC Epidemiology of Diabetes Interventions and Complications ELISA Enzyme-linked immunosorbent assay ENDIT European Nicotinamide Diabetes Intervention Trial ETDRS Early Treatment Diabetic Retinopathy Study ETF Enteral tube feeding EUCLID study EURODIAB Controlled Trial of Lisinopril in Insulin-Dependent Diabetes Mellitus FEV(1) Forced expiratory volume in one second FOOD Feed or ordinary diet trial

viii

Abbreviations

FSH Follicle-stimulating hormone GABA Gamma-aminobutyric acid G-CSF Granulocyte–colony stimulating factor GDM Gestational diabetes mellitus GFD Gluten-free diet GFR Glomerular filtration rate GI Glycaemic index GIK Glucose insulin potassium GIST Glucose Insulin in Stroke Trial GLP-1 Glucagon-like peptide-1 HAAF Hypoglycaemia associated autonomic failure HAIR-AN syndrome HyperAndrogenism, Insulin Resistance and Acanthosis Nigricans HbA1c Glycosylated haemoglobin HDL High-density lipoprotein HELLP syndrome Haemolysis, Elevated Liver enzymes, Low Platelets HERS Hormone Estrogen-Progestin Replacement Study HHS Hyperosmolar hyperglycaemic state HLA Human leucocyte antigen HOPE Heart Outcomes Protection Evaluation study HOT study Hypertension Optimal Treatment study HPS Heart Protection Study HRT Hormone replacement therapy ICU Intensive care unit IFG Impaired fasting glucose IGF Insulin-like growth factor IgG Immunoglobulin G IGT Impaired glucose tolerance IHD Ischaemic heart disease IMT Intima–media thickness INR International normalized ratio IRS Insulin resistance state IRMA Intraretinal microvascular abnormality ISDN Isosorbide dinitrate IV Intravenous IVF in vitro fertilization LAD Left anterior descending LDH Lactate dehydrogenase LDL Low-density lipoprotein

LIFE study Losartan Intervention For Endpoint reduction in hypertension LIPID study Long-term Intervention with Pravastatin in Ischaemic Disease study LH Leuteinizing hormone MA Microaneurysm MDI Multiple daily injections MDRD study Modification of Diet in Renal Disease Study MIDD Maternally inherited diabetes and deafness MO Macular oedema MODY Maturity-onset diabetes of youth MRA Magnetic resonance angiography MRFIT Multiple Risk Factor Intervention Trial MRI Magnetic resonance imaging MRSA Methicillin-resistant Staphylococcus aureus NAOIN Non-arteritic optic ischaemic neuropathy NASCET North American Symptomatic Carotid Endarterectomy Trial NGF Nerve growth factor NHANES National Health and Nutrition Evaluation Study NMR Nuclear magnetic resonance NO Nitric oxide NTD Neural tube defects NRT Nicotine replacement therapy OAD Oral antidiabetic agent oGTT Oral glucose tolerance test OSA Obstructive sleep apnoea PAD Peripheral arterial disease PARP Poly-ADP-ribose polymerase PCI Percutaneous coronary intervention PCOS Polycystic ovarian syndrome PDE Phosphodiesterase PDGF Platelet-derived growth factor PEDF Pigment Epithelial-Derived Factor PEG Percutaneous endoscopic gastrostomy PKC Protein kinase C PPAR Peroxisome proliferator-activated receptor PPP Primary Prevention Project PROGRESS Perindopril PROtection aGainst Recurrent Stroke Study RAS Renin–angiotensin system RANKL Receptor Activator of Nuclear factor Kappa B Ligand

S E C T I O N

O N E

01

Prevention and Diagnosis 1

Preventing type 1 diabetes

2

Preventing type 2 diabetes

3

Diabetes risk after the menopause

4

Genetic diabetes syndromes (MODY)

5

Screening and impaired glucose tolerance

6

Type A/B diabetes and insulin resistance

P R O B L E M

1 Preventing Type 1 Diabetes Case History The parent of a 4-year-old boy with type 1 diabetes consults you wanting to know if there is anything he can do to prevent a future child developing the condition. He already has an 8-year-old daughter with diabetes and there is a strong family history of autoimmune thyroid disease on both his and his wife’s side of the family. They are contemplating having a third child. Is there any evidence that type 1 diabetes is preventable? Is there any general advice the parents can usefully follow? Can we predict the onset of type 1 diabetes?

Background Preventing or curing type 1 diabetes is one of the holy grails for those who research autoimmune disease or treat patients with diabetes. The disease typically presents in childhood, currently necessitates lifelong use of insulin injections and exposes the indi© Atlas Medical Publishing Ltd, 2006

2

§01 Prevention and Diagnosis vidual to increased risk of vascular complications. The risk of type 1 diabetes in the general population is about 1 in 300, and this is increased up to 20-fold in first-degree relatives. Genetic markers do not provide an accurate prediction of diabetes, with only 5% of those with susceptibility markers actually developing the disease. However, the fact that the disease has a long latent period and that the pre-diabetic phase can be identified by measuring islet cell antibodies or by assessing beta cell function yields an opportunity for preventative therapy. The results of trials using non-specific immunosuppression in the 1980s were disappointing with only temporary improvements in insulin production demonstrated. Type 1 diabetes in children became much more common in the course of the 20th century.1 In fact, available evidence suggests that the disease was quite uncommon, although generally fatal, in children during the 19th century. This, along with the geographical variation in the prevalence of childhood diabetes that is not accounted for by variations in the prevalence of susceptible genotypes, strongly suggests that environmental factors are important.2 The wide variation in incidence rates applies much more to childhood than to adult type 1 diabetes.3 It is not surprising that there has been intensive research into environmental triggers for diabetes that might be modified, or into safe and effective nutritional or immunological manipulations that might decrease risk of developing the disease (Figure 1.1). Recent evidence suggests that most parents of children at risk of type 1 diabetes will attempt preventative measures,4 and it is increasingly important for health professionals to be able to enter into a balanced discussion with parents and would-be parents. Both macronutrient and micronutrient components of the diet have received attention.5 A protective effect of breast-feeding has been proposed, but not confirmed in all

Factors Predisposing To Type 1 Diabetes

Level of Evidence

Genetic (including HLA)

*** * * ** * *

Non-breast-fed Early exposure to cows’ milk Low vitamin D status Viral infection Rapid weight gain in childhood The Following Do Not Appear To Modify Risk Childhood vaccination Treatment with nicotinamide Oral insulin therapy

*** ** * Fig.1.1

Strong evidence supported by multiple well-conducted and randomized clinical studies Reasonable evidence supported by clinical studies (not randomized) Some evidence supported by observational studies and expert opinion

Factors predisposing to type 1 diabetes. HLA = human leucocyte antigen.

1 Preventing type 1 diabetes

3

studies. Breast-feeding may afford protection through early oral exposure to human milk (inducing tolerance to insulin; see below), through protection against infectious agents, and by decreasing the risk of excessive weight gain in infancy. The latter is also probably a trigger for diabetes during adolescence. On the other hand, early exposure to cows’ milk may increase risk through exposure to bovine insulin or
-casein, the latter being a known immunomodulatory protein contained in cows’ milk. Bottle-feeding can also be associated with excessive weight gain. Amongst micronutrient components of the diet, nitroso compounds (related to streptozotocin), nitrates and nitrites, all used as preservatives in meat products, have been considered. Variations in vitamin D status may be another reason for the geographical variation in the incidence of type 1 diabetes. Vitamin D has important regulatory effects on the immune system. A protective effect of cod liver oil (a source of both vitamin D and long-chain n-3 fatty acids, which are also anti-inflammatory) was shown against childhood diabetes in the recent study reported by the Norwegian Childhood Diabetes Study Group.6 Certain infectious agents, including enteroviruses, have been associated with development of diabetes in animal models and in rare cases of human diabetes. This has led to worries that childhood vaccination, particularly with live attenuated vaccines, may be a risk factor for type 1 diabetes. A Danish study, along with other recent evidence, has gone a long way to dispel worries on this score; Hviid and colleagues7 studied a cohort including all Danish children born between 1990 and 2000, and found no evidence of any association between childhood vaccinations and diabetes. On the contrary, the vaccines may be protective by limiting the effect of potentially diabetogenic infections, particularly rubella.

Recent Developments 1

Vitamin B3 (niacin) consists of nicotinic acid and nicotinamide. The latter is tolerated in high doses, and has been shown to decrease the incidence of diabetes in streptozotocin-treated animals, and in non-obese diabetic mice. Some early preclinical studies showed promise for the agent. The vitamin inhibits poly-ADP-ribose polymerase (PARP), an enzyme involved in DNA repair. Activation of PARP leads to depletion of intracellular nicotinamide adenine dinucleotide. This depletion of cellular energy stores may predispose to cell damage, including in the pancreatic beta cell. The European Nicotinamide Diabetes Intervention Trial (ENDIT)8 was a randomized, double-blind, placebo-controlled trial in which 552 islet cell antibody-positive firstdegree relatives of patients with diabetes took either nicotinamide or placebo. There was no difference in the incidence of diabetes during the five years of the trial (82 vs 77 cases, respectively).

2

Autoimmunity directed at insulin epitopes is one of the critical driving forces in the pathogenesis of type 1 diabetes. In animal models, exposure to mucosal insulin induces tolerance and thus decreases risk of diabetes. This mechanism is of particular interest because of the recent developments of insulin formulations which are active after oral or nasal administration. The Diabetes Prevention Trial-Type 1 reported recently.9 In this trial, a large number of first- and second-degree relatives of patients with diabetes were screened for pre-diabetes. Those found to be positive were ran-

4

§01 Prevention and Diagnosis domized to receive either oral insulin or placebo. Again, there was no difference in the incidence of new diabetes between the control and the treatment groups. 3

The prospects of gene therapy for diabetes are improving rapidly. Approaches to introduce a functioning insulin-producing mechanism in glucose-responsive cells have been considered. The genetic susceptibility to diabetes is mainly through class II histocompatibility alleles. Recent experiments in non-obese diabetic mice have been carried out to replace diabetes-prone genes with those that are protective.10

Conclusion There is not, currently, any way to accurately predict which individuals are going to get diabetes, or to prevent its occurrence. Family history is a major risk factor, increasing susceptibility by up to 20-fold, and there might be a slight bias towards males developing diabetes. Epidemiological data strongly support a role for environmental influences, especially for childhood diabetes. There is no evidence currently to support specific preventative measures. Breast-feeding should be promoted for its possible role in preventing type 1 diabetes, as well as its other health benefits. Efforts to limit excessive weight gain in infancy and adolescence should be promoted, as high body weight at these times may favour development of type 1 diabetes. Among the other nutritional factors, the best evidence is for a protective effect of vitamin D and supplementation should be considered (perhaps as cod liver oil) in areas where sunlight exposure is low. Finally, parents should be encouraged to have their children vaccinated as per normal childhood schedules— there is no evidence that vaccination predisposes to diabetes and it may be that, by decreasing infection with some agents, it actually protects.

Further Reading 1 Gale EAM. The rise of childhood type 1 diabetes in the 20th century. Diabetes 2002; 51: 3353–61. 2 Kukko M,Virtanen SM, Toivonen A, Simmell S, Korhonen S, Ilonen J, Simel O, Knip M.

Geographical variation in risk HLA-DQB1 genotypes for type 1 diabetes and signs of beta-cell autoimmunity in a high-incidence country. Diabetes Care 2004; 27: 676–81. 3 Kyvik KO, Nystrom L, Gorus F, Songini M, Oestman J, Castell C, Green A, Guyrus E, Ionescu-

Tirgoviste C, McKinney PA, Michalkova D, Ostrauskas R, Raymond NT. The epidemiology of Type 1 diabetes mellitus is not the same in young adults as in children. Diabetologia 2004; 47: 377–84. 4 Baughcum AE, Johnson SB, Carmichael SK, Lewin AB, She JX, Schatz DA. Maternal efforts to

prevent type 1 diabetes in at-risk children. Diabetes Care 2005; 28: 916–21. 5 Virtanen SM, Knip M. Nutritional risk predictors of beta cell autoimmunity and type 1 diabetes

at a young age. Am J Clin Nutr 2003; 78: 1053–67. 6 Stene LC, Joner G, Norwegian Childhood Diabetes Study Group. Use of cod liver oil during the

first year of life is associated with lower risk of childhood-onset type 1 diabetes: a large, population-based, case-control study. Am J Clin Nutr 2003; 78: 1128–34. 7 Hviid A, Stellfeld M, Wohlfahrt J, Melbye M. Childhood vaccination and type 1 diabetes. N Engl J

Med 2004; 350: 1398–1404.

2 Preventing type 2 diabetes

5

8 Gale EA, Bingley PJ, Emmett CL, Collier T. European Nicotinamide Diabetes Intervention Trial

(ENDIT): a randomised controlled trial of intervention before the onset of type 1 diabetes. Lancet 2004; 363: 925–31. 9 Skyler JS, Krischer JP, Wolfsdorf J, Cowie C, Palmer JP, Greenbaum C, Cuthbertson D, Rafkin-

Mervis LE, Chase HP, Leschek E. Effects of oral insulin in relatives of patients with type 1 diabetes: The Diabetes Prevention Trial-Type 1. Diabetes Care 2005; 28: 1068–76. 10 Tian C, Bagley J, Cretin N, Seth N, Wucherpfennig KW, Iacomini J. Prevention of type 1 diabetes

by gene therapy. J Clin Invest 2004; 114: 969–78.

P R O B L E M

2

Preventing Type 2 Diabetes

Case History You are consulted by a 43-year-old man who has a strong family history of diabetes. He is concerned because his father developed diabetes at the age of 56 and has recently (aged 60 years) had a lower limb amputation. Your patient is generally in good health. He has a body mass index of 28 kg/m2 and takes very little exercise as he has a busy job and a young family. He smokes 20 cigarettes per day, and has been noted to be mildly hypertensive although not requiring treatment at present. How would you advise him? Are we able to prevent development of type 2 diabetes? Is there a role for drug therapy?

Background Once the condition is established, it is extremely difficult to maintain tight control of blood glucose and other vascular risk factors in patients with type 2 diabetes. A number of very important studies have been published in the past three years demonstrating the potential for lifestyle interventions and drugs to either prevent diabetes, or at least to delay its onset. These studies, along with the acknowledged costs of managing patients with type 2 diabetes, have heightened awareness of the value of preventative measures. The best-known of the prevention studies is the Diabetes Prevention Program (DPP), carried out in 27 North American centres.1 In this study, 3234 non-diabetic patients with impaired glucose tolerance were randomly assigned to placebo, metformin (850 mg twice daily) or lifestyle intervention. The latter consisted of dietary advice plus at least 150 min-

6

§01 Prevention and Diagnosis utes of physical activity per week. After 2.8 years of follow-up, the incidence of diabetes was 11.0, 7.8 and 4.8 cases per 100 patient-years in the placebo, metformin and lifestyle groups, respectively. Metformin reduced the incidence of new diabetes by 31%, while lifestyle intervention reduced it by 58%. Some of the benefit associated with metformin use is lost after the drug is stopped. However, a recent washout study using the DPP cohort confirms that much of the benefit persists.2 A very recent cost–benefit analysis of this study confirmed that both interventions were cost effective.3 However, lifestyle intervention was much more cost effective with a cost, relative to placebo, of $1100 per quality-adjusted life-year, compared with $31 300 for metformin. The benefit of lifestyle intervention was confirmed in the Finnish Diabetes Prevention Study (DPS).4 Usual diabetes care was compared with a lifestyle intervention programme in 522 overweight, middle-aged subjects with impaired glucose tolerance. The lifestyle intervention group experienced greater weight loss and improved glycaemic and lipid parameters. The STOP-NIDDM trial5 (Study to Prevent Non-Insulin-Dependent Diabetes Mellitus) randomized 714 patients with impaired glucose tolerance to either placebo or acarbose, and followed them up for over three years. Forty-two per cent of patients in the placebo wing and 32% of patients taking acarbose developed diabetes. The decrease in new diabetes was highly significant, although the study has been criticized because of possible bias due to the large proportion of patients that did not complete their treatment regime. There is further evidence that drug treatment can prevent, or delay the onset of, diabetes from small studies using either sulphonylureas or the thiazolidinedione drug, troglitazone.6 One in five of the population in most developed countries is now obese, and this is the major factor underlying the global increase in diabetes prevalence in recent years. It is not surprising, therefore, that obesity has become an increasing focus for treatment and prevention of diabetes and cardiovascular disease. In the XENDOS study (XENical in the prevention of Diabetes in Obese Subjects), 3305 patients were treated with lifestyle intervention and randomized either to placebo or to treatment with the gastrointestinal lipase inhibitor, orlistat.7 After four years’ treatment, diabetes had developed in 9.0% of placebo patients and in 6.2% of orlistat-treated patients. Patients treated with orlistat also lost more weight and had improved lipid profiles. Again, and as with many long-term studies in this area, a relatively large proportion of patients did not complete the study. In summary, a number of recent studies confirm that both lifestyle interventions and drug treatments can reduce the incidence of new diagnoses of diabetes, and also improve some of the associated cardiovascular risk factors (Figure 2.1). Lifestyle intervention is clearly preferable, particularly if changes can be sustained long-term. Diet and exercise can also be cost-effective interventions. For those who do not succeed with lifestyle management, drug treatment appears to be both a safe and an effective option.

Recent Developments 1

Other drug groups used in the prevention of cardiovascular disease may affect the development of diabetes.6 Blockade of the renin–angiotensin system has now been shown in several studies, including the Heart Outcomes Protection Evaluation (HOPE) study, to modestly decrease incidence of diabetes. Lipid-lowering drugs may have a similar effect, perhaps by decreasing insulin resistance. For some patients, vig-

2 Preventing type 2 diabetes

7

Review Diet

Exercise Plan

Other Risk Factors (Smoking/Blood Pressure/Lipids/?Aspirin)

Normotensive

Hypertensive

Orlistat

?Metformin

Sibutramine

Figure shows suggested scheme for prevention of type 2 diabetes using lifestyle interventions and anti-obesity drugs.

Fig. 2.1

orous treatment of cardiovascular risk factors may be the best line of attack, and decreased risk of diabetes an important secondary benefit of treatment. 2

Individuals at high risk of vascular disease should have vigorous management of their multiple risk factors wherever possible. One of the largest randomized trials of lifestyle intervention conducted is the Multiple Risk Factor Intervention Trial (MRFIT). Recent data8 from nearly 13 000 men followed for up to seven years show, again, that diet and exercise can prevent diabetes. However, there were interesting differences between smokers and non-smokers; with lifestyle intervention, diabetes incidence was 18% lower in non-smokers but 26% higher in smokers. The exact reasons for this are not clear but use of antihypertensive drugs in smokers and weight gain associated with attempts to quit smoking are possible confounding factors.

3

The role of exercise in improving glucose tolerance is now well established. Traditionally, vigorous aerobic exercise was recommended but was often unpalatable or unachievable for overweight and untrained subjects. Now, almost any type of exercise—depending on the patient’s preferences and capabilities—is regarded as beneficial. Recent data from the Finnish Diabetes Prevention Study have confirmed the link between leisure-time physical activity and reduced risk of diabetes.9 Even lowintensity and walking activity were associated with improved glucose tolerance.

4

There is currently great focus on the effects of diets with differing macronutrient contents. Diets that are low glycaemic index, high in fibre and rich in wholegrain foodstuffs can improve glucose tolerance and diminish the risk of developing diabetes. These findings have been confirmed in a number of substantial studies published in the past two years. In one recent study involving over 36 000 Australian

8

§01 Prevention and Diagnosis men,10 consumption of a low glycaemic diet correlated strongly with a decreased risk of diabetes. Also, and in keeping with other studies, low dietary magnesium intake was also associated with increased risk of diabetes.

Conclusion Given the difficulty experienced in reducing the risk associated with type 2 diabetes once the condition has developed, it seems imperative to try to prevent the condition whenever the opportunity arises. Although the above patient is fit and healthy at present, he is at risk in the future of developing type 2 diabetes. Initial management should be with dietary advice from a registered dietician and the patient should be advised about the benefits of exercise. Even a modest increase in low-intensity activity might be of benefit. He should have a thorough assessment of his overall cardiovascular risk and, if necessary, receive treatment for poorly controlled risk factors. Given that he is healthy and young, he should be strongly advised to keep his weight down and to engage in regular physical activity. Once he commences drug therapy, he is likely to take it for life. He should be advised to stop smoking and offered smoking cessation support if needed. This will reduce his risk of cardiovascular events and may also decrease his risk of diabetes. His glycaemic status should be assessed by fasting blood glucose and, preferably, also with a random or postprandial measurement. Drug therapy—for example with metformin—could be considered if he has impaired glucose tolerance. The benefit is not likely to be as great as that with diet and exercise, and this should be repeatedly emphasized to the patient.

Further Reading 1 Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, Nathan DM.

Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002; 346: 393–403. 2 Diabetes Prevention Program Research Group. Effects of withdrawal from metformin on the

development of diabetes in the diabetes prevention program. Diabetes Care 2003; 26: 977–80. 3 Herman WH, Hoerger TJ, Brandle M, Hicks K, Sorensen S, Zhang P, Hamman RF, Ackermann

RT, Engelgau MM, Ratner RE. The cost-effectiveness of lifestyle modification or metformin in preventing type 2 diabetes in adults with impaired glucose tolerance. Ann Intern Med 2005; 142: 323–32. 4 Lindström J, Louheranta A, Mannelin M, Rastas M, Salminen V, Eriksson J, Uusitupa M,

Tuomilehto J. The Finnish Diabetes Prevention Study (DPS): Lifestyle intervention and 3-year results on diet and physical activity. Diabetes Care 2003; 26: 3230–6. 5 Chiasson JL, Josse RG, Gomis R, Hanefeld M, Karasik A, Laakso M. Acarbose for prevention of

type 2 diabetes mellitus: the STOP-NIDDM randomised trial. Lancet 2002; 359: 2072–7. 6 Padwal R, Majumdar SR, Johnson JA,Varney J, McAlister FA. A systematic review of drug

therapy to delay or prevent type 2 diabetes. Diabetes Care 2005; 28: 736–44. 7 Torgerson JS, Hauptman J, Boldrin MN, Sjöströöm L. XENical in the prevention of diabetes in

obese subjects (XENDOS) study: a randomized study of orlistat as an adjunct to lifestyle changes for the prevention of type 2 diabetes in obese patients. Diabetes Care 2004; 27: 155–61.

3 Diabetes risk after the menopause

9

8 Davey Smith G, Bracha Y, Svendsen KH, Neaton JD, Haffner SM, Kuller LH. Incidence of type 2

diabetes in the randomized multiple risk factor intervention trial. Ann Intern Med 2005; 142: 313–22. 9 Laaksonen DE, Lindström J, Lakka TA, Eriksson JG, Niskanen L, Wikström K, Aunola S,

Keinänen-Kiukaanniemi S, Laakso M,Valle TT, Ilanne-Parikka P, Louheranta A, Hämäläinen H, Rastas M, Salminen V, Cepaitis Z, Hakumäki M, Kaikkonen H, Härkönen P, Sundvall J, Tuomilehto J, Uusitupa M. Physical activity in the prevention of type 2 diabetes: the Finnish diabetes prevention study. Diabetes 2005; 54: 158–65. 10 Hodge AM, English DR, O’Dea K, Giles GG. Glycemic index and dietary fiber and the risk of

type 2 diabetes. Diabetes Care 2004; 27: 2701–6.

P R O B L E M

3

Diabetes Risk after the Menopause

Case History A 54-year-old Afro-Caribbean woman is referred to you. She is two years postmenopausal and type 2 diabetes was diagnosed eight months ago. Despite having visited the dietician three times since then, her body mass index remains high at 30 kg/m2. She takes atenolol 50 mg/day for hypertension, which is well controlled. Diabetes is treated by diet alone, and her glycosylated haemoglobin (HbA1c) is reasonable at 7.1%. Fasting cholesterol is 5.8 mmol/l and triglycerides 2.5 mmol/l. She has a strong family history of type 2 diabetes. How would you manage her diabetes and hypertension? Is her age and menopausal status relevant to her management? Is her racial background important? She wants to know whether she should consider hormone replacement therapy

Background Compared with men, women are relatively protected from cardiovascular disease except when they are post-menopausal or they have diabetes. Sex steroids have important roles in regulating lipid metabolism, endothelial function, blood vessel tone and other aspects of vascular function. Menopause is associated with a relatively abrupt decrease in circulating oestrogen. There is no comparable process in men. Since the general population is aging, and women spend an increasing proportion of their life in an oestrogen-deficient

10

§01 Prevention and Diagnosis state in which they are at risk of atherosclerotic disorders, management of cardiovascular risk in the peri- and post-menopausal periods is of particular importance. The period of declining ovarian function leading up to the menopause, the perimenopause, is associated with declining sex steroid levels and important alterations in body composition. Thus total and visceral adiposity increase, and bone mineral density decreases. The change in fat mass and distribution may relate to decreased lipolysis and increased activity of lipoprotein lipase. Weight gain around the menopause is greater in women from more deprived socio-economic backgrounds and in those who do not smoke, do not exercise regularly and have never used HRT. In a prospective 9-year study of women during the menopausal transition, Guthrie et al.1 demonstrated that mood changes and decreased quality of life appeared to contribute to the changes in body composition and cardiovascular risk profile around the menopause. HRT is not currently recommended for prevention of cardiovascular disease. Although benefits in risk-markers have been documented, there is debate about which oestrogen, which progestogen, or which combination, and which route of administration. Set against the possibility of a marginal benefit in cardiovascular disease prevention, there is undoubtedly increased risk of thromboembolic events and breast cancer. Moreover, two important trials—the Women’s Health Initiative (WHI) and the Hormone EstrogenProgestin Replacement Study (HERS)—actually reported increased cardiac events in the short term. A recent large, Swedish study2 appears to confirm that oestrogen use can improve cardiovascular risk profile and there are now several lines of evidence that either oral or transdermal oestrogen may improve insulin sensitivity and slow the progress of the metabolic syndrome, thus retarding development of diabetes in those at risk.3 The impact of diabetes on cardiovascular risk is higher for women than it is for men. In a recent Finnish study,4 the event rate per 1000 patient-years was 11.6 for non-diabetic men and 1.8 for non-diabetic women, while comparable event rates for males and females with diabetes were 36.3 and 31.6, respectively. In the recent Study of Women’s health Across the Nation (SWAN),5 differences between insulin sensitivity and beta cell function were compared in groups of pre- or peri-menopausal women from differing racial backgrounds. Insulin sensitivity was lower in African-Americans compared with other racial groups, while beta cell function was relatively preserved in this group. Thus measures to improve insulin sensitivity, including weight loss, should be the approach of choice in this group.

Recent Developments 1

Increased abdominal obesity in women is linked with insulin resistance and with markers of inflammation that predispose to ischaemic heart disease and other complications of obesity (Figure 3.1).6 Although visceral obesity does not account for all of the increased risk associated with the post-menopausal state, it is an important therapeutic target, and regular exercise goes a long way to ameliorate the fat accumulation and accompanying risk factors.7

2

Attempts to improve health and deal with cardiovascular risk factors should not wait until the menopause. Recent data from the Nurses Health Study8 demonstrate that

3 Diabetes risk after the menopause

11

40

42.9

Percent type 2 diabetes

35 45 %

30

40

25

35

20

30

15 10

25 10.5

20

Percent type 2 diabetes

45 %

5 0

15 10

High IR

5.3

5

Low IR

0 Low VAT

High VAT

Contributions of visceral adipose tissue (VAT) and insulin resistance (IR) to risk of diabetes. Postmenopausal women were screened for diabetes using an oral glucose tolerance test. Diabetes was particularly prevalent in women who had both increased visceral adipose tissue and insulin resistance. *P 320 mOsm/kg*
Only mild ketonaemia and ketonuria *calculated as: [(2  plasma Na+) + plasma glucose]

Plasma urea is not included in the calculation of effective osmolality because it is freely permeable in and out of the intracellular compartment. Coma is often associated with serum osmolality of >400 mOsm/kg. Other common biochemical abnormalities at presentation are hypernatraemia and disproportionately raised urea levels. Initial laboratory tests should also include a complete blood count with differentials, bacterial cultures of blood, urine and other tissues, serum amylase, chest radiograph, electrocardiogram and serum creatinine kinase in patients with prolonged immobilization to exclude rhabdomyolisis. Differences in biochemical abnormalities associated with DKA and HHS are shown in Table 8.1 below. Table 8.1 Comparison of blood biochemistry abnormalities in DKA and HHS

Glucose (mmol/l)

Normal range

DKA

HHS

4.2–6.4

>14

>34

Arterial pH

7.35–7.45

7.3

Bicarbonate (mmol/l)

22–28

15

Effective serum osmolality (mOsm/kg)

275–295

320

Sodium (mmol/l)

136–145

134 (1.0)

149 (3.2)

Potassium (mmol/l)

3.5–5.0

4.5 (0.13)

3.9 (0.2)

Lactate (mmol/l)

0.56–2.2

2.4

3.9 1

Values for sodium and potassium in DKA and HHS are mean (standard deviation). Source: adapted from Chiasson et al. 2003.

Patients with DKA tend to produce larger increases in some counter-regulatory hormones—catecholamines, growth hormones and cortisol—but not glucagon, inducing a greater degree of insulin resistance compared with patients with HHS. The treatment goals for HHS are improving circulatory volume and tissue perfusion, reducing serum glucose and plasma osmolality and correcting electrolyte imbalances, as well as identifying and treating precipitating factors (Figure 8.1). The choice of initial replacement fluid in patients with HHS remains debated. Some authorities advocate the use of hypotonic fluid (e.g. 0.45% saline) from the outset, whereas others advocate the initial use of isotonic fluid (0.9% saline) in the first hour followed by the use of 0.45% or 0.9% saline, depending on corrected plasma sodium and the haemodynamic status of the patient. In the absence of clear evidence, it would be reasonable to firstly correct extracellular fluid depletion by infusing isotonic saline at a rate of 15–20 ml/kg/h (which is hypotonic to the patient’s extracellular fluid and remains restricted to the extracellular fluid

32

§02 Acute Diabetes

HHS

Initiate fluid replacement with 0.9% saline, followed by 0.45% saline. Watch for heart failure. In elderly patients CVP monitoring may be required (see text)

Initiate insulin treatment (0.15 unit/kg) (see text) aim for plasma glucose lowering at a rate of 14 mmol/l.

Close monitoring of U+E, urine output

When patient is taking orally: Stop intravenous insulin, refer to diabetes specialist nurse, identify predisposing factors to prevent future HHS admissions. In patients not previously on insulin, clarify if patient’s glycaemia is suitable to be treated by oral hypoglycaemic agent or diet only

compartment) in the first one to two hours until vital signs are stabilized, followed by the administration of hypotonic saline at a rate of 4–14 ml/kg/h with the aim of restoring deficits in both intracellular and extracellular compartments as well as ongoing fluid losses.2 Dextrose should be added to replacement fluids when plasma glucose is around 14 mmol/l, with administration of 5% or even 10% dextrose depending on the patient’s sodium level. Correction of the patient’s dehydration and hyperglycaemic state may result

8 Hyperosmolar hyperglycaemic state

33

in a transient false elevation of the observed plasma sodium, but when serum sodium is corrected for glucose levels—calculated as ([observed sodium] + 1.6  [(plasma glucose –5.5)/5.5])—the level of serum sodium may, in fact, be stable or gradually improving. It is also important that changes in plasma osmolality do not exceed 3 mOsm/kg/h. In patients with renal or cardiac dysfunction, it is important to maintain close monitoring of fluid balance, occasionally by central venous pressure and/or pulmonary artery pressure monitoring, in order to avoid iatrogenic fluid overload. Insulin treatment should be initiated while the patient is being rehydrated with an initial bolus of 0.15 unit/kg (or 10 units soluble insulin) followed by continuous intravenous insulin infusion at a rate of 0.1 unit/kg/h. Failure to reduce plasma glucose level by 3–4 mmol/l/h is often due to inadequate hydration. The appropriate level of hydration reduces the amount of counter-regulatory hormones such as cortisol, growth hormones, glucagon and catecholamines, produced in response to stress, making cells more responsive to insulin. If hydration status is acceptable, insulin rate should be increased hourly until a decrease in plasma glucose of 3–4 mmol/l/h is achieved. Patients are considered to have recovered from HHS if effective osmolality is